EFFECT OF α-KLOTHO ON GROWTH HORMONE ACTION IN CHRONIC KIDNEY DISEASE

The α-klotho, identified in α-klotho mutant mice (kl/kl mice) exhibiting symptoms of early aging, and exists in membrane and secreted forms. The kl/kl mice or α-klotho knockout (KO) mice subsequently display growth retardation and severe aging phenotypes, leading to an average lifespan of around 60 days. The kl/kl mice have shown reduced vesicle numbers in growth hormone (GH) -producing cells, resulting in GH resistance and a lack of weight gain even with GH administration. GH is secreted from the anterior pituitary gland and exerts various metabolic functions via insulin-like growth factor 1 (IGF1), which is produced mainly in the liver. In pediatric GH deficiency, secretory α-klotho blood levels are reduced, and GH treatment increases blood levels. Children with chronic kidney disease (CKD) is associated with changes in the GH/IGF1 axis, including impaired GH signaling and growth retardation associated with GH-resistance. The kidney is the organ with the highest α-klotho expression, and both α-klotho expression levels in the kidney and serum α-klotho concentrations decrease with the progression of CKD. Thus, we speculate that the decrease in α-klotho may be involved in GH resistance in patients with CKD. In the present study, we focused on the relationship between GH action and the anti-ageing hormone α-klotho and hypothesised that GH resistance in CKD is associated with α-klotho deficiency.

GH (4 mg/kg body weight) was administered to 4-week-old mice and to an adenine-induced pediatric nephropathy mouse model to assess the GH-induced α-klotho, IGF1 and GH receptor expression responses. Next, to identify nutrients that induce α-klotho expression, we fed the mice zinc-supplemented feed for one week and examined the expression of α-klotho. Finally, zinc-supplemented feed was administered to kidney disease model mice for three weeks, followed by dissection after GH administration. Expression of α-klotho and IGF-1 in the kidneys and growth rate were assessed.

We investigated the induction of α-klotho expression following GH administration in 4-week-old mice. GH increased the expression of α-klotho mRNA in the kidney, pituitary gland, femur, and calvaria. Particularly in the kidney and blood, GH administration led to an increase in α-klotho protein expression. Next, mice models of adenine-induced pediatric kidney disease were generated and treated with GH, but no induction of GH receptor, IGF1, and α-klotho mRNA expression was observed, indicating GH resistance, suggesting that reduced α-klotho expression may suppress GH action. α-klotho maintenance and increase could improve GH resistance, we investigated nutrients that increase α-klotho expression, and found that zinc increased α-klotho expression in the kidney without inhibiting growth. Finally, kidney disease model mice were treated with a zinc-supplemented diet for 3 weeks, followed by GH. In the zinc-supplemented diet group, an increase in renal α-klotho and IGF1 mRNA expression was observed and a recovery of growth inhibition was observed compared to the normal diet group.

These findings suggest that α-klotho is downstream of GH and may be involved in GH resistance in CKD.